Our long range goals are to define, in specific chemical and physiologic terms, the mechanisms by which the pregnant and post-partum uterus regulates the metabolism of its principal connective tissue protein, collagen. This protein is absolutely required by the uterus for the structural integrity of the organ during pregnancy; thus it is necessary to precisely regulate the level and distribution of collagen in the tissue during gestation. After delivery, the protein is degraded during the general involution of the uterus occurring in all mammals. The degradation of collagen in the uterus absolutely requires the action of a specific collagenase, whose function it is to catalyze the crucial cleavages in collagen which initiate the process by which the protein is removed from the extracellular matrix. The specific approaches of these studies are to obtain, in pure form, the biological molecules which are required for this process to occur in an orderly fashion; these include the zymogen of collagenase itself, an activator of this zymogen, and an inhibitor of active collagenase, all of which are produced by the uterus for the purpose of regulating the rate and the direction of collagen degradation in the organ. These molecules are in the process of being purified, their chemical nature investigated, and their interactions studied. The results of these investigations should provide fundamental information regarding the mechanisms by which collagen degradation is accomplished in the uterus and, very likely, in other tissues as well. In addition, the physiologic processes by which the appearance of these molecules in the uterus is regulated will be studied in two principal in vitro systems: in cells and in organized explants in culture. The nature of the mechanisms whereby collagenase production and activity can be induced, modulated in situ, and terminated when no longer required are all under study. Such mechanisms involve the physiologic activities of important gestational hormones such as progesterone and relaxin, as well as the role of physical distension of the uterine myometrium as an important modifier of uterine connective tissue metabolism. By understanding the molecules involved in these processes and the way in which their giological activity is regulated, normal pregnancy can be better understood and more rationally managed. The information can also be applied to complicated pregnancies, in which fetal health may be endangered by uterine dysfunction.